The response of the cyclic 3',5'-nucleotide phosphodiesterase(PDE) system of perfused rat heart to epinephrine, glucagon, 1-methyl-3-isobutyl-xanthine, insulin, thyroxine, and dibutyryl cyclic AMP will be investigated to determine whether this system undergoes regulatory or compensatory alterations. The activity, distribution, cooperative properties and kinetic parameters of PDE associated with different subcellular fractions will be determined in control and treated hearts. Alterations in the distribution or equilibrium between soluble forms of PDE will be examined using density gradient ultracentrifugation and chromatography on DEAE-cellulose under controlled conditions. Potential correlations between the changes in tissue cyclic nucleotide levels and specific perturbations in the PDE system will be investigated in order to determine their significance and relevance to the cyclic nucleotide system.